A normalities of cerebral cortical development are frequently associated with pediatric epilepsy, especially the most severe types of epilepsy [l]. Little is known about how these disorders come about, largely because knowledge of normal cortical development is limited. For example, it is difficult to determine whether known cortical malformations are genetically inherited, or reflect exposure of the fetal brain to infections or teratogens. Retroviral-mediated gene transfer is a method that may allow a step-by-step analysis of stages of cortical development in animal models. A library of retroviral markers, each carrying distinct genetic tags, allows cells derived from single progenitor cells to be identified as they divide, migrate, and differentiate. Previous application of the retroviral library method has provided important insights into how cortical cells achieve their final identities and suggests these hypotheses: Hypothesis 1: Cerebral cortical cells obtain their final cellular identity through a series of developmental steps. The cortex derives ultimately from primitive progenitors capable of producing many cell types. However, the cortex also contains short-lived progenitors that produce specific cell types. The first specific aim is to analyze the changing behavior of cerebral cortical progenitor cells using new retroviral libraries that allow both morphological analysis of neuronal types and PCR analysis of clonal relationships. Hypothesis 2: Progenitors at different stages of development differ not only in the cell types they produce, but also in patterns and substrates of cell migration. Whereas some primitive cells migrate rapidly, perpendicular to radial glial fibers, other progenitors may undergo cell division without substantial migration. Finally, postmitotic neurons migrate long distances in close apposition to radial glia. The second specific aim is to identify systematically the changing patterns of cortical cell migration and relate patterns of cell migration to patterns of cell division. Hypothesis 3: The cortex develops from two cell layers, the cortical plate and the subplate; the two layers have distinct migration patterns, and may have different patterns of lineage. The third specific aim is to compare lineage patterns in subplate and cortical plate cells by labeling cortical progenitors at earlier stages than previously possible, and analyzing lineage relationships of the oldest cortical cells. Hypothesis 4: Distinct forebrain structures may share common patterns of cell identity determination. The fourth specific aim is to examine cell lineage patterns in the olfactory bulb, striatum, and hippocampal cortex, in order to test whether similar patterns of cell lineage hold in non- neocortical forebrain structures. Completion of these specific aims should advance the cellular understanding of how cerebral cortical progenitor cells divide and migrate. This understanding can then form a framework for the interpretation of epilepsy-associated disorders of cortical development, allowing the development of hypotheses about prenatal causes of epilepsy and other neurological disorders.